Erythroid progenitor cell survival, proliferation and differentiation are regulated by erythropoietin and other factors in the local environment. Sensitivity of erythroid differentiation to stressed conditions is demonstrated using a two phase erythroid culture system for erythroid differentiation of human CD34+ cells that shows decreased proliferation and increased fetal hemoglobin production under conditions of low erythropoietin or with low oxygen tension leading to cytotoxicity. Conversely, while erythropoietin supplementation in sickle cell patients treated with hydroxyurea was shown to increase fetal hemoglobin, increasing erythropoietin level or erythropoietin signaling in erythroid differentiating CD34+ cell cultures increased proliferation and hemoglobin positive cells without increasing fetal hemoglobin, suggesting that increased erythropoietin signaling increases erythrocyte production but alone may be insufficient to alter the hemoglobin program to increase fetal hemoglobin. In mice, erythropoietin treatment is accompanied by improved glucose tolerance and decreased blood glucose level, linking erythropoietin stimulated erythropoiesis with metabolic glucose response. The increased proliferation with increased erythropoietin in erythroid cultures is also accompanied by increased glucose uptake. While the bone marrow microenvironment has the potential to influence erythropoiesis, erythropoietin treatment in mice also affects bone and bone marrow. Accompanying erythropoietin stimulated erythropoiesis is a decrease in bone marrow adipocytes and bone loss. Patients with central diabetes insipidus that lack the antidiuretic hormone vasopressin show an intermittent anemia, suggesting that vasopressin may exhibit an associated erythropoietic activity. To examine the activity of vasopressin on erythroid differentiation, human CD34+ cells isolated from peripheral blood of healthy donors were differentiated in a two phase erythropoietic culture system. Addition of vasopressin increased erythroid cell number beginning mid-way through differentiation, further increasing by 40 to 50% of control at the end of the culture period of 12 days. At culture day 9, vasopressin increased erythropoietin stimulated increase in STAT5 activation, and by day 12, vasopressin alone increased STAT5 activation comparable to erythropoietin alone, providing further evidence that vasopressin contributes to erythroid proliferation/differentiation of human erythroid progenitor cells.